tbuckley/cabot-search huggingface dataset:
Abstract 6065: ASF1B potentiates stem cell traits and tumor progression in hepatocellular carcinoma via histone H3.3-dependent transcriptional reprogramming
Authors: Xiaona Fang, Beilei Liu, Shan Liu, Yu Zhang, Lanqi Gong, Qian Yan, Xinyuan Guan
Journal: Cancer Research (2022)

Abstract Hepatocellular carcinoma (HCC) is one of the frequently diagnosed cancers worldwide and has emerged as the main cause of cancer-related death with a very poor prognosis, which is closely related to cancer stem cell (CSC), a subset of cells known to be a root of tumor recurrence, metastasis, and chemoresistance in HCC. However, the characteristics of CSCs in hepatocellular carcinoma (HCC) are still elusive. Our previous in vitro hepatocyte differentiation model revealed that the expression of anti-silencing function 1B histone chaperone (ASF1B) was remarkably upregulated in the stem cell-like stages. In HCC patients, ASF1B was highly expressed in cancer tissues compared with normal counterparts and was positively correlated with poor survival. Functional assays indicated that ASF1B could considerably promote the self-renewal, growth, and metastasis of HCC both in vitro and in vivo. Mechanistically, ASF1B could directly bind to histone H3 Variant H3.3 and enhance its incorporation into the promoter regions of certain stemness- and metastasis-associated genes including SOX9, KLF4, and TBX3, contributing to their augmented transcriptional and protein expression levels. H3.3 knock-down decreased the expression of these stemness and metastasis-associated genes, eliminating the stemness and oncogenic properties of ASF1B. Overall, our study revealed that ASF1B could facilitate HCC stemness and progression via H3.3-dependent transcriptional reprogramming. ASF1B might be a novel diagnostic and prognostic biomarker for HCC patients. Citation Format: Xiaona Fang, Beilei Liu, Shan Liu, Yu Zhang, Lanqi Gong, Qian Yan, Xinyuan Guan. ASF1B potentiates stem cell traits and tumor progression in hepatocellular carcinoma via histone H3.3-dependent transcriptional reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6065.
Abstract 5846: Comprehensive genomics-based screening of novel therapeutic targets and biomarkers for lung cancer
Authors: Yataro Daigo, Atsushi Takano, Yusuke Nakamura
Journal: Cancer Research (2022)

Abstract As the number of patients with lung cancer who show good response to standard therapies is limited, new molecular targeted therapies and biotherapies with predictive biomarkers are urgently required. We have been developing molecular therapies targeting oncoproteins with their companion diagnostics as follows, i) To identify overexpressed genes in 120 lung cancers by gene expression microarray analysis of 27,648 genes, ii) To verify the candidate genes for their scarce expression in 23 normal organs, iii) To validate the clinicopathologic significance of their protein expression by tissue microarray covering hundreds of lung cancers including non-small cell lung cancers (NSCLCs), and iv) To examine whether they are important for the growth or invasion of cancer cells by using siRNAs and/or small molecule inhibitors. By this screening system, we identified dozens of candidate target molecules and selected a gene encoding protein with a GAP domain, LAPG1 (lung cancer-associated protein with Gap domain 1). Immunohistochemical analysis showed that LAPG1 expression was observed in 69.9% of lung cancers. Moreover positivity of LAPG1 expression was associated with poor prognosis for lung cancer patients. Knockdown of LAPG1 expression by siRNAs suppressed growth of lung cancer cells. Introduction of LAPG1 increased the invasive activity of mammalian cells, indicating that LAPG1 could be a prognostic biomarker and therapeutic target for lung cancers. Our comprehensive genomics-based screening might be useful to select the novel biomarkers and therapeutic targets for developing small molecules, antibodies, nucleic acid drugs, and immunotherapies against lung cancer. Citation Format: Yataro Daigo, Atsushi Takano, Yusuke Nakamura. Comprehensive genomics-based screening of novel therapeutic targets and biomarkers for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5846.
Abstract 176: Development of PDX-derived spheroids using LifeGel, an innovative 3D cell culture technology
Authors: Agnieszka Pietrzyk, Emilie Indersie, Olivier Deas, Jean-Gabriel Judde, Marcin Krzykawski, Stefano Cairo
Journal: Cancer Research (2022)

Abstract One of the biggest challenges in preclinical oncology is the lack of models faithfully recapitulating the physiological and pathophysiological features of the native tumor. PDXs (Patient-Derived Xenografts), developed in immune-compromised mice, have proven their relevance in the study of aberrations leading to the development and progression of cancer, to the mechanisms linked to tumor resistance and to the identification of novel therapies. Despite being a fundamental step to generate new knowledge on cancer, the use of PDXs shows some technical disadvantages such as long engraftment time and/or low growth rate, thus raising economic and ethical concerns. Huge efforts are being done to develop cell-based alternatives systems reproducing the tumor complexity combined with suitable methods. To this aim, we have developed 50+ PDX-derived cell lines (PDXDCs) from our proprietary 200+ PDX collection. These lines are currently used as two-dimensional (2D) cultures to perform drug screening in an affordable, timewise, and cost-effective way. While well designed, drug-tailored 2D screenings can predict drug behavior in vivo, they present limitations as they are unable to reproduce cell-cell and cell-extracellular matrix interactions, two important parameters that contribute to the regulation of drug accessibility and oxygen diffusion in vivo. To encompass those limitations and give access to a wider range of experimental methods we have generated three-dimensional (3D) cell culture models by taking advantage of LifeGel technology, consisting of protein-based hydrogels that modulate matrix density and stiffness to mimic the organ of origin-specific extracellular environment. Thanks to its versatility we successfully developed spheroid cultures from PDXDCs from various indications, including breast cancer cells from different histological subtypes. Tumor cells plated on LifeGel adopted 3D spheroid-like structures in a few days. These structures showed heterogeneous morphology and size depending on the tumor type and the hydrogel composition. As spheroids can be passaged in vitro by digestion, we could easily expand them and perform drug screening that will be presented and compared to 2D and in vivo results. The aim of this project is to develop a collection of PDX-derived spheroids recapitulating PDXs characteristics. This collection will give the opportunity to perform high-content drugs screening to select the best candidate drugs to be retained for further preclinical in vivo studies. Citation Format: Agnieszka Pietrzyk, Emilie Indersie, Olivier Deas, Jean-Gabriel Judde, Marcin Krzykawski, Stefano Cairo. Development of PDX-derived spheroids using LifeGel, an innovative 3D cell culture technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 176.
Abstract 1674: FGF8 as a modulator of Wilms' tumor <i>in vitro</i> growth and longevity
Authors: Garrett Cooper, Benjamin Lee, Nate Smyth, Karuna Mittal, Taylor Lawrence, Hunter Jonus, Jenny Shim, Kelly Goldsmith, Andrew Hong
Journal: Cancer Research (2022)

Abstract Wilms’ tumor is the most common pediatric renal tumor accounting for 6-7% of all childhood cancers. Development of faithful Wilms’ tumor cell lines is needed to identify novel therapeutics. Currently, established Wilms’ tumor cell lines that are suitable for high throughput studies only represent anaplastic Wilms, a rare subtype. In contrast, cell lines representing the more common favorable histology Wilms’ tumor (FHWT) often have poor proliferative capacity and are unable to passage long-term (e.g. &amp;gt;20 passages). For this reason, there is a need to establish robust cell lines representing FHWT. We hypothesize that there are core factors missing from the cell culture medium which prevent proper growth signaling and proliferation. We first performed bulk RNA-sequencing from patients and associated cell lines at Aflac Cancer and Blood Disorders Center with an underlying diagnosis of FHWT. Transcriptomic analyses showed that the reduced growth and proliferation in these FHWT cell lines may be due to reduced presence of the mitogenic fibroblast growth factor 8 (FGF8) in the cell culture environment as compared to the tumor environment. Wilms’ tumor has notably high FGF8 expression levels compared to all other pediatric tumors, implicating FGF8 as a potential driving factor in tumor maintenance. To characterize the phenotypic effects of FGF8 reintroduction in short term FHWT cell lines, we both endogenously overexpressed FGF8 via a lentiviral vector and ectopically added recombinant FGF8 to the cell culture medium. Qualitatively, endogenous overexpression of FGF8 induced distinct morphological changes in cells, converting the enlarged and flattened cells into more focal cells resembling proliferative early passage cells. Quantitatively, overexpression of FGF8 in one favorable histology cell line led to an increased rate of cellular proliferation and extended the cellular longevity by seven passages (47% above baseline). RNA-sequencing analysis of these FGF8 overexpressing cells implicated the anti-apoptotic gene, NTSR1, and an extracellular matrix protein, SNED1, as potential downstream targets of FGF8 overexpression. However, ectopic addition of recombinant FGF8 protein to the cellular medium had less pronounced effects, with seemingly cell-line specific effects. These data demonstrate FGF8 as possibly being required for survival in certain Wilms’ tumor cell lines that can be modulated to influence in vitro proliferation and longevity. Citation Format: Garrett Cooper, Benjamin Lee, Nate Smyth, Karuna Mittal, Taylor Lawrence, Hunter Jonus, Jenny Shim, Kelly Goldsmith, Andrew Hong. FGF8 as a modulator of Wilms' tumor in vitro growth and longevity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1674.
Abstract 1905: Accelerating clinically-translatable discoveries using a network- and RNA-based precision-oncology framework
Authors: Alessandro Vasciaveo, Min Zou, Juan M. Arriaga, Francisca Nunes de Almeida, Eugene F. Douglass, Michael Shen, Andrea Califano, Cory Abate-Shen
Journal: Cancer Research (2022)

Abstract Despite recent advances, prioritizing therapy at the individual patient level remains challenging. In fact, inter-patient tumor heterogeneity remains one of the major challenges in cancer therapy, making it difficult to optimize available treatments on an individual patient basis. Likewise, the systematic prediction of drug sensitivity in vivo is still a major challenge in translational research, where targeted therapeutics are currently selected based on the presence of either actionable oncogene dependencies or aberrant cellular mechanisms. A further challenge is the limited availability of models that faithfully recapitulate the biology, complexity, and heterogeneity of human tumors, including their interaction with a conserved microenvironment and a competent immune system. To address these challenges, we introduce OncoLoop, a highly-generalizable, network-based precision medicine framework to triangulate between available mouse models, human tumors, and large-scale drug perturbational assays with in vivo validation to predict personalized treatment. OncoLoop requires only transcriptomic data (i.e., RNA-seq profiles) and leverages regulatory network analysis to (a) identify cognate models based on conservation of patient-specific Master Regulator (MR) proteins and (b) prioritize drugs based on their ability to invert the activity of MR proteins (MR-inverters), using drug perturbation profiles in cognate cell lines. As proof-of-concept, we applied OncoLoop to prostate cancer using a series of genetically engineered mouse models (GEMMs) that capture a broad range of phenotypes, including metastatic, castration-resistant and neuroendocrine disease. Indeed, &amp;gt;70% of patients in published cohorts had at least one high-fidelity matched GEMM. Drugs targeting shared Master Regulator dependencies of a patient and its cognate GEMM(s) were predicted using perturbational profiles of &amp;gt;300 drugs in MR-matched cell lines, resulting in an 80% validation rate in GEMM allografts and human xenografts. This network-based approach is highly generalized and can be applied to both cancer and non-cancer-related contexts. Citation Format: Alessandro Vasciaveo, Min Zou, Juan M. Arriaga, Francisca Nunes de Almeida, Eugene F. Douglass, Michael Shen, Andrea Califano, Cory Abate-Shen. Accelerating clinically-translatable discoveries using a network- and RNA-based precision-oncology framework [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1905.
Abstract 3107: Identifying therapeutic vulnerabilities in HR-positive, HER2-negative advanced breast cancer patient-derived xenograft models refractory to CDK4/6 inhibition
Authors: Nicole M. Kettner, Juliana Navarro-Yepes, Tuyen N. Bui, Xiayu Rao, Jing Wang, Funda Meric-Bernstam, Kelly K. Hunt, Debu Tripathy, Khandan Keyomarsi
Journal: Cancer Research (2022)

Abstract Background: Clinically, the addition of CDK4/6 inhibitors (e.g. palbociclib) to endocrine therapy (ET) significantly delays progression of advanced hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer patients. However, most patients develop resistance and progress following long-term treatment. Thus, an ongoing clinical challenge has been the identification of biomarkers that predict response to CDK4/6 inhibitors. There is also an unmet need to identify actionable targets for patients who have progressed. Currently, there are no clinically useful biomarkers to predict response and/or resistance to anti-CDK4/6 therapy. Hence, the goal of our study was to identify the therapeutic vulnerabilities of CDK4/6 inhibitor resistant patient derived xenograft (PDX) models and identify key markers that longitudinally correlate with development of resistance and inform new treatment directions. Methods: We obtained 4 different PDX models, two from patients who progressed after 2-4 months on treatment with palbociclib plus ET (i.e. intrinsic resistance) and the other two who developed resistance over time (i.e. acquired resistance) with disease progression between 12-18 months while on palbociclib plus ET. To elucidate mechanisms of resistance, we performed genome-wide expression analysis via RNA-sequencing. Results: The molecular assessment of the PDX models revealed different transcriptomic signatures for intrinsic resistance compared to acquired resistance. We identified 3,386 upregulated and 2,829 downregulated significant differentially expressed genes (DEGs) in the acquired compared to intrinsic resistant PDX models. Further, gene set enrichment analysis (GSEA) revealed enrichment of distinct driver pathways in the acquired-compared to the intrinsic resistant models. Conclusions: Collectively, these results have identified potential unique targets for intrinsic and acquired resistance to guide treatment strategies. Thus, our ongoing studies are geared towards identifying and targeting distinct therapeutic vulnerabilities of intrinsic and acquired resistance to palbociclib. Citation Format: Nicole M. Kettner, Juliana Navarro-Yepes, Tuyen N. Bui, Xiayu Rao, Jing Wang, Funda Meric-Bernstam, Kelly K. Hunt, Debu Tripathy, Khandan Keyomarsi. Identifying therapeutic vulnerabilities in HR-positive, HER2-negative advanced breast cancer patient-derived xenograft models refractory to CDK4/6 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3107.
<i>Notes from the Field:</i> COVID-19–Associated Mortality Risk Among Long-Term Care Facility Residents and Community-Dwelling Adults Aged ≥65 Years — Illinois, December 2020 and January 2022
Authors: Daniel Lee, Catherine Counard, Angela Tang, Sarah Brister, Ngozi Ezike
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

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Abstract 899: Effects of innate immune deaminase deregulation on initiation and progression of myeloproliferative neoplasms
Authors: Jane Marie Isquith, Adam Mark, Jessica Pham, Mary Donohoe, Luisa Ladel, Catriona Jamieson
Journal: Cancer Research (2022)

Abstract Inflammatory cytokine responsive APOBEC3 cytidine deaminases have been studied extensively with regard to innate immunity and more recently during cancer evolution. However, the mechanisms by which the APOBEC3 enzymes promote cancer initiation and progression in the malignant microenvironment remains to be investigated, especially in hematopoietic malignancies. Through whole genome and whole transcriptome sequencing analyses of MPN patient samples FACS sorted into stem and progenitor populations, we have found a cell type and context specific nature of these enzymes, notably the upregulation of APOBEC3C (A3C) in the high-risk Myelofibrosis (MF) stem cell population as compared to normal aged counterparts. Through lentiviral overexpression of each APOBEC3 enzyme, we can now study the effects of changes in APOBEC3 transcript level in relation to the known changes in expression seen in many cancers, focusing on the upregulation of A3C. Using these techniques, we have identified novel RNA and DNA editing targets, as well as differential gene expression patterns of each APOBEC3 in normal CD34+ cord blood and aged normal bone marrow. Gene set enrichment analysis (GSEA) performed on this dataset has exposed numerous deregulated pathways brought on by exaggerated levels of APOBEC3, including changes in splicing pathways. In addition, novel identification of the relationship between A3C and ADAR1, another innate immune deaminase, has important implications in initiation and prognosis of MPNs. Both A3C and ADAR1 transcript levels are elevated in high risk MF stem cells, and co-immunoprecipitation studies reveal a direct binding of the enzymes. Furthermore, we are able to study the detailed effects of editing by both A3C and ADAR1 using editase-deficient mutant constructs, allowing for a mechanistic look into the role of these deaminases and their deregulation in vitro and in vivo using patient samples and humanized mouse models. This novel connection, as well as the role of A3C in initiation and progression of hematopoietic malignancies will continued to be studied using this system to elucidate effects on proliferation, differentiation, self-renewal, and changes to the cell cycle, in hopes of creating both a marker of early detection and potentially a druggable target. Citation Format: Jane Marie Isquith, Adam Mark, Jessica Pham, Mary Donohoe, Luisa Ladel, Catriona Jamieson. Effects of innate immune deaminase deregulation on initiation and progression of myeloproliferative neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 899.
Preexisting comorbidities shape the immune response associated with severe COVID-19
Authors: Stefanie Kreutmair, Manuel Kauffmann, Susanne Unger, Florian Ingelfinger, Nicolás Gonzalo Núñez, Chiara Alberti, Donatella De Feo, Sinduya Krishnarajah, Ekaterina Friebel, Can Ulutekin, Sepideh Babaei, Benjamin Gaborit, Mirjam Lutz, Nicole Puertas Jurado, Nisar P. Malek, Siri Göpel, Peter Rosenberger, Helene A. Häberle, Ikram Ayoub, Sally Al-Hajj, Manfred Claassen, Roland Liblau, Guillaume Martin-Blondel, Michael Bitzer, Antoine Roquilly, Burkhard Becher
Journal: Journal of Allergy and Clinical Immunology (2022)

Comorbidities are risk factors for development of severe coronavirus disease 2019 (COVID-19). However, the extent to which an underlying comorbidity influences the immune response to severe acute respiratory syndrome coronavirus 2 remains unknown.Our aim was to investigate the complex interrelations of comorbidities, the immune response, and patient outcome in COVID-19.We used high-throughput, high-dimensional, single-cell mapping of peripheral blood leukocytes and algorithm-guided analysis.We discovered characteristic immune signatures associated not only with severe COVID-19 but also with the underlying medical condition. Different factors of the metabolic syndrome (obesity, hypertension, and diabetes) affected distinct immune populations, thereby additively increasing the immunodysregulatory effect when present in a single patient. Patients with disorders affecting the lung or heart, together with factors of metabolic syndrome, were clustered together, whereas immune disorder and chronic kidney disease displayed a distinct immune profile in COVID-19. In particular, severe acute respiratory syndrome coronavirus 2-infected patients with preexisting chronic kidney disease were characterized by the highest number of altered immune signatures of both lymphoid and myeloid immune branches. This overall major immune dysregulation could be the underlying mechanism for the estimated odds ratio of 16.3 for development of severe COVID-19 in this burdened cohort.The combinatorial systematic analysis of the immune signatures, comorbidities, and outcomes of patients with COVID-19 has provided the mechanistic immunologic underpinnings of comorbidity-driven patient risk and uncovered comorbidity-driven immune signatures.